April 25, 2014

Decade-Long Study Unlocks Full Genetic Map Of The Deadly Tsetse Fly

A nearly decade-long study involving more than 140 scientists from around the world has resulted in the successful mapping of the tsetse fly’s genetic code. Researchers involved in the study say this could open the door to scientific breakthroughs that could potentially end the scourge of sleeping sickness in sub-Saharan Africa.

The tsetse fly, scientifically known as Glossina morsitans, is the sole carrier of a disease that threatens the livelihood of millions of people and devastates livestock herds. Publishing their study in the journal Science, the researchers said they have revealed the genetic adaptations that allow the fly to have such a unique biology and transmit disease to both humans and animals.

The genetic blueprint of the tsetse fly, which is slightly larger than a common housefly, is deemed a “parts list” of what the organism is made from. By offering access to this blueprint, the authors expect research into the biology of the fly to be accelerated with the ultimate goal of improving tsetse control methods and the development of new control strategies.

“This is a major milestone for the tsetse research community,” study lead author Geoffrey M. Attardo, a research scientist at the Yale School of Public Health, said in a statement. “Our hope is that this resource will facilitate functional research and be an ongoing contribution to the vector biology community.”

The effort to fully map the tsetse has resulted in the publication of eight additional research articles that expand on the genomic data using functional genomics methods. Aside from the Science paper, the additional articles are being published under the title “Tsetse Genome Biology Collection” across the PLOS journal community.

TSETSE DISEASES

The tsetse fly spreads two parasitic diseases: human African trypanosomiasis (HAT), known as sleeping sickness, and Nagana, which infects both humans and animals. Throughout sub-Saharan Africa, 70 million people are at risk of deadly infection. The World Health Organization lists HAT as one of neglected tropical diseases and has targeted the disease for eradication since last year. A better understanding of the fly’s DNA will go a long way in helping researchers find a way to interfere with its ability to transmit disease.

The fly’s ability to spread disease relies on an advanced sensory system that allow them to track down potential hosts either through smell or sight. The study’s parts list opens a new door in the potential design of prevention strategies that could reduce the number of deaths and illnesses associated with HAT and Nagana.

"Tsetse flies carry a potentially deadly disease and impose an enormous economic burden on countries that can least afford it by forcing farmers to rear less productive but more trypanosome-resistant cattle." said Dr Matthew Berriman, co-senior author from the Wellcome Trust Sanger Institute. "Our study will accelerate research aimed at exploiting the unusual biology of the tsetse fly. The more we understand, the better able we are to identify weaknesses, and use them to control the tsetse fly in regions where human African trypanosomiasis is endemic."

While there are drugs that can be used to combat sleeping sickness, they are expensive, have numerous side effects, and are difficult to administer throughout rural Africa where the disease is most pronounced. However, if the disease is left untreated, it is fatal in all patients.

In all, the team is composed of 146 scientists from 78 research institutes across 18 countries. They analyzed the genome of the tsetse fly and its 12,000 genes that control protein activity. The long-term study will provide the research community with a free-to-access resource that will help accelerate improved tsetse-control strategies.

"Our study will accelerate research aimed at exploiting the unusual biology of the tsetse fly. The more we understand, the better able we are to identify weaknesses, and use them to control the tsetse fly in regions where human African trypanosomiasis is endemic," said Berriman.

STUDY CHALLENGES

However, unlocking the secrets of the tsetse fly was not easy.

The team had to overcome numerous challenges across technical, biological and economical borders in order to decipher the complete tsetse genome. As with most genome projects the team had to limit their analysis to a single genetic line in order to improve the assembly of small fragments of sequence data – thousands of letters of code – into large scaffolds that contain millions of letters of code. This quickly became an issue because only a small amount of genetic material is obtainable from each specimen, and unlike most insects, one tsetse female gives birth to very few offspring. The tsetse genome contains in the neighborhood of 366 million letters of code, which is equivalent to about 10 percent of those in the human genome.

Serap Aksoy, a professor with Yale’s School of Public Health, helped initiate the genome study when she and a small group of scientists concluded that progress against sleeping sickness would be stymied unless biological and chemical underpinnings of the organism were completely understood.

“We are very happy to finally reach the finish line,” Aksoy said. “Our hope is that tsetse research will now enjoy broader participation from the vector community and lead to improved and novel methods to eliminate disease.”

The tsetse fly is related to the fruit fly, which has been a favorite for study for more than a hundred years. Despite being related to the fruit fly, the tsetse genome is twice as large. And the reproductive biology of the tsetse is quite unusual. Unlike most other insects that lay eggs, the tsetse female gives birth to live young that have developed to a large size by feeding on specialized glands in the mother.

In the study, the researchers found a set of visual and odor proteins that seem to drive the fly’s key behavioral responses such as searching for hosts and for mates. Also uncovered was the photoreceptor gene rh5, the missing link that explains the fly’s attraction to blue/black colors. This behavior has already been exploited for the development of traps to help reduce the spread of disease.

"Though human African trypanosomiasis affects thousands of people in sub-Saharan Africa, the absence of a genome-wide map of tsetse biology was a major hindrance for identifying vulnerabilities," said Aksoy. "This community of researchers across Africa, Europe, North America and Asia has created a valuable research tool for tackling the devastating spread of sleeping sickness."

The tsetse fly also has an armament of salivary molecules that are essential for feeding on blood. The team discovered one family of genes – tsal genes – that are particularly salivary glands of the tsetse fly. These genes allow the fly to counteract the responses from the host to stop blood-feeding. This discovery along with several others are explored in depth in the eight PLOS research papers that accompany the Science paper.

"This information will be very useful to help develop new tools that could reduce or even eradicate tsetse flies," Dr John Reeder, Director of the Special Programme for Research Training in Tropical Diseases at WHO, said in a statement. "African sleeping sickness is understudied, and we were very pleased to help bring together so many research groups to work collaboratively with the one shared goal in sight - the elimination of this deadly disease."

The genome study cost around $10 million and was funded over the years from multiple public and private sources, including Wellcome Trust, WHO’s Special Programme for Research and Training in Tropical Diseases, and the Ambrose Monell Foundation. The genome was sequenced and assembled at the Wellcome Trust Sanger Institute. The study got its start with initial seed funding from WHO.

Data from the project is currently being hosted by Vectorbase and is available to the public for download or for direct analysis on the website using a comprehensive set of browsing, searching and analysis tools.